Synthesis of 2-deoxy-2-fluoro-arabinose derivatives

ABSTRACT

A process for deoxofluorinating a C2-hydroxyl group of a furanose, includes: (a) mixing the furanose and a deoxofluorinating agent in a solvent to form a reaction mixture, and (b) heating the reaction mixture to greater than about 50° C. The process provides deoxofluorinated products, such as 2-fluoro-arabinoses, in yields of at least 80% of theoretical.

CROSS-REFERENCE TO RELATED APPLICATIONS

Not applicable.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

BACKGROUND OF THE INVENTION

This invention relates to processes for deoxyfluorinating the pentosesugar of a nucleoside to form the corresponding 2-β-fluoro-arabinosecompounds.

The development of safe, efficient, and simple methods for selectiveincorporation of fluorine into organic compounds has become a veryimportant area of technology. It is of particular importance withrespect to the deoxyfluorination of the pentose sugar component of anucleoside to form 2-β-fluoro-arabinose compounds, which have been shownto exhibit potent anti-tumor and anti-viral activity. See, e.g., Wrightet al., 13(2) J. Med. Chem. 269-72 (1970); Fanucchi et al., 69(1) CancerTreat. Res. 55-9 (1985); Fox et al., Medicinal Chemistry Advances, p. 27(Pergamon Press, NY, 1981); and Fox et al., “Herpes Viruses and VirusChemotherapy,” Pharmacological and Clinical Approaches, p. 53, (ExcerptaMedica, Amsterdam, 1985). For example, 2′-fluoro-5-iodo-ara-cytosine(FIAC), 2′-fluoro-5-methyl-ara-uracil (FMAU), 2′-fluoro-5-methyl-arauracil (FMAU) and 2′-fluoro-5-ethyl-ara uracil (FEAU) are active againstDNA viruses, according to Lopez et al., 17(5) J. Antimicrob. AgentsChemother. 803-6 (1980); and Lin et al., 221 Science 519 (1983).Although certain 2′-fluoropurine derivatives are cytotoxic, others havebeen shown to possess anti-HIV activity. See, e.g., Chu et al., 37 Chem.Pharm. Bull. 336 (1989); and Marquez et al., 33 J. Med. Chem. 978(1990). This is due to the fact that fluorine strategically positionedat sites of synthetic drugs and agrochemical products can significantlymodify and/or enhance their biological activities. Fluorine mimicshydrogen with respect to steric requirements and contributes to analteration of the electronic properties of the molecule. Increasedlipophilicity and oxidative and thermal stabilities have been observedin such fluorine-containing compounds.

The conversion of the C—O bond to the C—F bond, which is referred toherein as deoxofluorination, represents a viable method to produceselectively fluorinated organic compounds. Deoxofluorination representsone technique which has been widely used for the selective introductionof fluorine into organic compounds. See, e.g., Boswell et al., 21 Org.React. 1 (1974). A list of the deoxofluorination methods generally usedto fluorinate organic compounds to date includes: nucleophilicsubstitution via the fluoride anion; phenylsulfur trifluoride;fluoroalkylamines; sulfur tetrafluoride; SeF₄; WF₆; difluorophosphoranesand the dialkylaminosulfur trifluorides (DAST). The most common reagentof this class is diethylaminosulfur trifluoride, Et-DAST or simply DAST.

The DAST compounds have proven to be useful reagents for effectingdeoxofluorinations. These reagents are conventionally prepared byreaction of N-silyl derivatives of secondary amines with SF₄. Incontrast to SF₄, DAST compounds are liquids which can be used atatmospheric pressure and at near ambient to relatively low temperature(room temperature or below) for most applications. Deoxofluorination ofalcohols and ketones is particularly facile and reactions can be carriedout in a variety of organic solvents (e.g., CHCl₃, CFCl₃, glyme,diglyme, CH₂Cl₂, hydrocarbons, etc.). Most fluorinations of alcohols aredone at a temperature within the range of −78° C. to room temperature.Various functional groups are tolerated, including CN, CONR₂, COOR(where R is an alkyl group), and successful fluorinations have beenaccomplished with primary, secondary and tertiary (1°, 2°, 3°) allylicand benzylic alcohols. The carbonyl to gem-difluoride transformation isusually carried out at room temperature or higher. Numerous structurallydiverse aldehydes and ketones have been successfully fluorinated withDAST. These include acyclic, cyclic, and aromatic compounds. Eliminationdoes occur to a certain extent when aldehydes and ketones arefluorinated and olefinic byproducts are also observed in theseinstances.

However, while the DAST compounds have shown versatility in effectingdeoxofluorinations, there are several well-recognized limitationsassociated with their use. The compounds can decompose violently andwhile adequate for laboratory synthesis, they are not practical forlarge scale industrial use. In some instances, undesirable byproductsare formed during the fluorination process. Olefin eliminationbyproducts have been observed in the fluorination of some alcohols.Often, acid-catalyzed decomposition products are obtained. Moreover, thetwo-step synthesis employed with DAST compounds renders these relativelycostly compositions only suitable for small scale syntheses.

The inventor and his colleagues have previously disclosed that otheraminosulfur trifluorides, such as bis(2-methoxyethyl)aminosulfurtrifluoride, are much safer to use than DAST and related aminosulfurtrifluorides. See Lal et al., 64(19) J. Org. Chem. 7048 (1999); Lal etal., J. Chem. Soc. Chem. Commun. p. 215 (1999); U.S. Pat. No. 6,080,886and U.S. patent application Ser. No. 08/939,635 filed Sep. 29, 1997.Compared to DAST compounds, bis(2-methoxyethyl)aminosulfur trifluoridesprovide more thermally stable fluorine-bearing compounds which haveeffective fluorinating capability with far less potential of violentdecomposition and attendant high gaseous byproduct evolvement, withsimpler and more efficient fluorinations. Furthermore,bis(2-methoxyethyl)aminosulfur trifluorides can efficiently effect thetransformation of hydroxy and carbonyl functionalities to thecorresponding fluoride and gem-difluoride respectively.

It has been observed that the direct replacement of a leaving group atthe 2′-position of a pyrimidine nucleoside by the fluoride ion iscomplicated by neighboring-group participation of the carbonyl group ofthe base, resulting in the formation of the anhydronucleoside. See Fox,18 J. Pure Appl. Chem. 223 (1969). In the synthesis of 2′-fluoropurines,attempts to replace a C₂ protecting group (e.g., triflate) with fluorideresulted in base cleavage and formation of olefinic byproducts. SeePankiewicz et al., 64 J. Fl. Chem. 15 (1993). It has also been observedthat the direct deoxofluorination of the 2′-hydroxyl of some purinederivatives by diethylaminosulfur trifluoride (DAST) afford only lowyields of products even when a large excess of the fluorinating agent isused. See Pankiewicz et al., 57 J. Org. Chem. 553 (1992).

The synthesis of 2′-fluoro-substituted nucleosides is currently carriedout by condensation of the appropriate 2-fluoro sugar derivative withthe nucleoside base. See Pankiewicz et al., 15 J. Fl. Chem. 64 (1993).However, the fluoro sugar is not easily accessible since its preparationoften involves lengthy multi-step and low yielding procedures. SeeReichmann et al., 42 J. Cardohydr. Res. 233 (1975). The nucleophilicdisplacement of a leaving group by fluoride at C-2 of furanosides isoften accompanied by elimination reactions resulting in olefinicbyproducts. See Tann et al., 50 J. Org. Chem. 3644 (1985). Tann et al.reported on a three-step synthesis of2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose via a2-O-imidazolylsulfonate leaving group using KHF₂ as the source offluoride. Tann et al. found that the direct replacement of theC₂-hydroxyl of this sugar by F with diethylaminosulfur trifluoride(DAST) failed.

Despite the findings in Tann et al., it has been shown that DAST hasbeen used successfully for the deoxofluorination of hydroxy groups ofsix-membered ring sugars and the C₃ hydroxyl of five-membered ringsugars (i.e., furanoses). See Welch et al., Fluorine in BioorganicChemistry, p. 131 (John Wiley and Sons, 1991). Additionally, theprocedure of Tann et al. was improved upon by Chou et al. (37 Tett.Lett. 1 (1996)) where triethylamine poly(hydrogen fluoride) was used asthe source of fluoride.

Accordingly, there remains a need in the art for a process effective todeoxofluorinate the C₂-hydroxyl group of furanoses.

All references cited herein are incorporated herein by reference intheir entireties.

BRIEF SUMMARY OF THE INVENTION

The invention provides a process for deoxofluorinating a C₂-hydroxylgroup of a furanose. The process comprises mixing the furanose and adeoxofluorinating agent in a solvent to form a reaction mixture, andheating the reaction mixture to greater than about 50° C.

Also provided are products produced by the process of the invention.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

Not applicable.

DETAILED DESCRIPTION OF THE INVENTION

A preferred process of the invention comprises deoxyfluorinating ahydroxylated ring carbon of a sugar with a fluorinating agent in thepresence of a solvent. A preferred embodiment of the invention is shownin Equation I:

where each of R, R′ and R″ is independently a protecting group or agroup that does not react with the deoxofluorinating agent in theinventive process (unless it is desired to deoxofluorinate more than onecarbon per molecule). Preferred protecting groups include esters,ethers, sulfonates, acetals and orthoesters. Particularly preferredprotecting groups include benzoyl, trityl and triflate.

In embodiments, it is preferred to further modify the product ofdeoxofluorination to replace the protecting groups with hydrogen and/orto convert the sugar into a 2′-deoxy-2′-fluoro-arabinoside, wherein R ofEquation I is a pyrimidine (e.g., cytosine, uracil or thymine) or apurine (e.g., adenine or guanine). Methods for coupling the sugar with anucleoside base are known in the art. Thus, the invention provides animproved process for providing 2′-fluoropurines and2′-fluoropyrimidines. The most preferred embodiments of the inventiveprocess provide 2-fluoro-arabinose compounds and derivatives, includingthose previously shown to exhibit potent anti-tumor and anti-viralactivity.

The preferred reactant to be deoxofluorinated is a five-membered ringsugar (i.e., a furanose) bearing a hydroxyl group solely at C₂, whereinany additional hydroxyl groups have been replaced with a protectinggroup. Ribofuranoses are preferred reactants, but the invention is notlimited thereto. For example, furanoses wherein C₃ is unsubstituted(i.e., is bonded to two hydrogens) are also suitable reactants. Thechoice of reactant is largely influenced by the desired product.Ribofuranose reactants are most preferred as they provide2-fluoro-arabinose products, such as2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranose,3-deoxy-2-fluoro-1-methoxy-5-trityl-α-D-arabinofuranose, and2-fluoro-1,3,5-tribenzoyl-α-L-arabinofuranose, which are preferredproducts of the invention.

After having the hydroxyl groups other than the C₂ hydroxyl groupprotected (or selecting a sugar inherently containing groups other thanthe C₂ hydroxyl group which are not reactive with the deoxofluorinatingagent), the sugar to be deoxofluorinated is reacted with adeoxofluorinating agent in a solvent. Deoxofluorinating agents suitablefor use in the invention include, e.g., diethylaminosulfur trifluoride(DAST), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor™ reagentavailable from Air Products and Chemicals, Inc., Allentown, Pa.),perfluorobutanesulfonyl fluoride,2-chloro-1,2,3-trifluoroethyldiethylamine (Yarovenko-Raksha reagent),and hexafluoroisopropyl diethylamine (Ishikawa reagent) and otheraminosulfur trifluorides. Preferably, the deoxofluorinating agent isbis(2-methoxyethyl)aminosulfur trifluoride.

The deoxofluorination reaction of the present invention is conducted inthe presence of a solvent. Preferably, the solvent does not react withthe fluorinating agent. More preferably, the solvent is selected fromthe group consisting of hydrocarbons, halocarbons, ethers, amides,esters and mixtures thereof. Most preferably, the solvent is toluene.The solvent is preferably non-polar.

Preferably, the deoxofluorination is conducted at temperatures rangingfrom room temperature to less than the boiling point of the solvent. Itis particularly preferred to combine the reactants in the solvent atroom temperature and allow the reaction to progress at room temperature(i.e., without active heating) for a period of time before raising thetemperature above 50° C.. The mixing time without active heating isabout 30 to 90 minutes, preferably about 1 hour. After this initialreaction period, the reaction mixture is preferably heated to greaterthan about 50° C., more preferably about 90° C., and mixed for anadditional 90 minutes or more, preferably about 2 hours.

Thus, in particularly preferred embodiments, the reactants are combinedin the solvent at room temperature, mixed without heating for about 1hour, and heated to about 90° C. with continued mixing for an additional2 hours or so.

The reaction product is preferably isolated from the reaction mixture byquenching the reaction with an aqueous base, extracting the product inan organic solvent and distilling the solvent. The aqueous base ispreferably NaHCO₃. The solvent used for extraction is preferably thesame solvent used as a medium for the reaction.

The product can be further purified by conventional techniques, such aschromatography or recrystallization.

Unlike conventional methods, the instant invention provides2-fluoro-arabinose compounds in a yield ranging from about 83% to about98% of theoretical.

The invention will be illustrated in more detail with reference to thefollowing Examples, but it should be understood that the presentinvention is not deemed to be limited thereto.

EXAMPLES Example 1 Fluorination of 1,3,5-tribenzoyl-α-D-ribofuranosewith Bis(2-methoxyethyl)aminosulfur Trifluoride

A suspension of 1,3,5-tribenzoyl-α-D-ribofuranose (225 mg, 0.5 mmol) intoluene (5 mL) was treated with bis(2-methoxyethyl)aminosulfurtrifluoride (110 mg, 0.5 mL) under nitrogen in a 50 mL 3-neck roundbottom flask equipped with a N₂ inlet, a rubber septum, a stopper and amagnetic stir bar. The mixture was stirred at room temperature for 1hour. It was then heated to 90° C. and kept at this temperature for anadditional 2 hours. The solution was cooled to 0° C. and treated withsaturated NaHCO₃ solution. After CO₂ evolution ceased, the mixture wasextracted with toluene, dried (Na₂SO₄), filtered and evaporatedin-vacuo. The residue was purified by chromatography on silica gel inethyl acetate/hexanes (1/4) to obtain 215 mg (95% yield) of pure2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose (Formula I,below, where Bz represents C—O-Phenyl).

The NMR spectral characteristics obtained were ¹H NMR (CDCl₃) d 8.2-7.95(m, 6H), 7.75-7.5 (m, 3H), 7.5-7.35 (m, 6 H), 6.75 (d, 1H, J=9 Hz), 5.65(dd, 1H, J=18 Hz, 3 Hz), 5.35 (d, 1H, J=48 Hz), 4.85-4.75 (m, 1H),4.75-4.65 (m, 2H). ¹⁹F NMR (CDCl₃) d−191.

Example 2 Fluorination of 1,3,5-tribenzoyl-α-D-ribofuranose with DAST

Deoxofluorination was performed as in Example 1, with DAST (80 mg, 0.5mL) substituted for bis(2-methoxyethyl)aminosulfur trifluoride. Thereaction yielded 217 mg (96% yield) of2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose (Formula I,above). The NMR spectral characteristics were the same as in Example 1.

Example 3 Fluorination of 3-deoxy-1-methoxy-5-trityl-α-D-ribofuranosidewith Bis(2-methoxyethyl)aminosulfur Trifluoride

Deoxofluorination of 3-deoxy-1 -methoxy-5-trityl-α-D-ribofuranoside (388mg, 1 mmol) was performed as in Example 1, using 243 mg (1.1 mmol) ofbis(2-methoxyethyl)aminosulfur trifluoride in 5 mL of toluene. Thereaction yielded 324 mg (83% yield) of3-deoxy-2-fluoro-1-methoxy-5-trityl-α-D-arabinofuranose (Formula II,below) as a mixture of anomers.

The NMR (¹H NMR (CDCl₃)) spectral characteristics obtained were: (majoranomer) d 7.5-7.3 (m, 4.5 H), 7.3-7.1 (m, 4.5 H), 7.1-7.0 (m, 2.25 H),5.0 (d, 0.75 H), 4.8 (dm, 0.75 H), 4.35-4.10 (m, 0.75), 3.3-3.0 (m, 1.5H), 3.3 (s, 2.25H), 2.4-2.1 (m, 0.75H), 1.9-1.7 (m, 0.75 H). ¹⁹F NMRd−180. ¹H NMR (CDCl₃) (minor anomer), d d 7.5-7.3 (m, 1.5 H), 7.3-7.1(m, 1.5 H), 7.1-7.0 (m, 0.75 H), 5.0 (d, 0.25 H), 4.9 (dm,0.25 H),4.35-4.10 (m, 0.25 H), 3.7-3.5 (m, 0.5H), 3.3 (s, 0.75H) 1.8-1.3 (m,0.5H). ¹⁹F NMR (CDCl3) −180.

Example 4 Fluorination of 1,3,5-tribenzoyl-α-L-ribofuranoside withBis(2-methoxyethyl)aminosulfur Trifluoride

Deoxofluorination of 1,3,5-tribenzoyl-α-L-ribofuranoside (4.5 g, 10mmol) was performed as in Example 1, using 2.43 g (11 mmol) ofbis(2-methoxyethyl)aminosulfur trifluoride in 50 mL of toluene. Thereaction yielded 4.87 g (98% yield) of2-fluoro-1,3,5-tri-O-benzoyl-α-L-arabinofuranose, having spectralcharacteristics similar to the (D)-isomer product of Example 1.

Comparative Example

The procedure employed in the foregoing examples to prepare2-fluoroarabinose derivatives was found to be rather facile, despite theteachings of Tann et al., supra, to the effect that the directreplacement of the C₂-hydroxyl of 2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose by F with diethylaminosulfurtrifluoride (DAST) failed. An experiment was performed to confirm theresult reported by Tann et al.

A suspension of 1,3,5-tri-O-benzoyl-α-D-ribofuranose (225 mg, 0.5 mmol)in CH₂Cl₂ (5 mL) was treated with DAST (81 mg, 0.067 mL). The mixturewas stirred at room temperature to reflux. After 16 hours, a hard toresolve, complex mixture of fluorinated products was observed with anapproximately 40% yield of the desired 2-fluoro-arabinose.

It is apparent from the foregoing examples and comparative example thatthe inventive process is a simple, yet powerful, tool for obtainingdeoxofluorinated sugars, such as 2-deoxy-2-fluoro-arabinoses, andderivatives thereof, including nucleosides. The inventive process evenworks quite well with a 3-deoxyribose bearing an acid sensitive tritylgroup at C₅ and a methoxy group at the anomeric carbon (Example 3). Evenwith this compound, no elimination products were observed.

It has been noted that the process favors a relatively non-polarreaction medium, since in more polar solvents such as CH₃CN and DMF,none of the desired products were observed.

There has been some speculation in the literature on the mechanism ofdeoxofluorination of alcohols by aminosulfur trifluorides. While therehas been some NMR evidence for the formation of analkoxy-N,N-dialkylaminodifluorosulfurane intermediate, it was onlyrecently that such a specie was isolated and fully characterized. SeeSutherland et al., Chem. Commun. 1739 (1999). The stability of thedifluorosulfurane intermediate seems to be greater for alcohols that aremore sterically hindered. The results obtained in the fluorination ofthe 2-hydroxyribose derivatives in the present invention suggest that arelatively stable alkoxy-N,N-dialkylaminodifluorosulfurane interemediateis formed at lower temperatures as a result of the steric influence ofthe vicinal α-protecting groups. This is subsequently displaced byfluoride on heating to higher temperatures leading to the desired2′-fluoro product.

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A process for deoxofluorinating a C₂-hydroxylgroup of a furanose, said process comprising: mixing said furanose and adeoxofluorinating agent in a solvent to form a reaction mixture; andheating said reaction mixture; quenching said deoxofluorinating agent insaid heated reaction mixture to provide a quenched mixture; andisolating a deoxofluorinated product from said quenched mixture, whereina yield of said deoxofluorinated product is at least 80% of theoretical.2. The process of claim 1, wherein said yield is at least 95%.
 3. Theprocess of claim 1, wherein said mixing is conducted for 30 to 90minutes without active heating.
 4. The process of claim 1, wherein saidmixing is conducted for about 1 hour without active heating.
 5. Theprocess of claim 1, wherein said heating is conducted for at least 90minutes.
 6. The process of claim 1, wherein said heating is conductedfor about 2 hours.
 7. The process of claim 1, wherein said reactionmixture is heated to about 90° C.
 8. The process of claim 1, whereinsaid mixing is conducted for about 1 hour, and then said heating isconducted for about 2 hours at about 90° C.
 9. The process of claim 1,wherein said solvent is non-polar.
 10. The process of claim 1, whereinsaid solvent is at least one member selected from the group consistingof halocarbons, hydrocarbons, ethers, amides and esters.
 11. The processof claim 1, wherein said solvent is toluene.
 12. The process of claim 1,further comprising the step of substituting a protecting group for eachhydroxyl group of said furanose other than said C₂-hydroxyl group. 13.The process of claim 12, wherein said protecting group is at least onemember selected from the group consisting of esters, ethers, sulfonates,acetals and orthoesters.
 14. The process of claim 12, wherein saidprotecting group is at least one member selected from the groupconsisting of benzoyl, trityl or triflate.
 15. The process of claim 12,wherein said furanose an arabinofuranose.
 16. The process of claim 12,wherein said furanose is a ribofuranose.
 17. The process of claim 16,wherein said furanose is 1,3,5-tribenzoyl-α-D-ribofuranose,1,3,5-tribenzoyl-α-L-ribofuranose or3-deoxy-1-methoxy-5-trityl-α-D-ribofuranose.
 18. The process of claim16, wherein a product of said deoxofluorinating is a2-deoxy-2-fluoro-arabinofuranose.
 19. The process of claim 18, furthercomprising replacing a C₁ hydroxyl group with a pyrimidine or a purine.20. A 2′-deoxy-2′-fluoro-arabinofuranoside produced by the process ofclaim
 19. 21. A 2-deoxy-2-fluoro-arabinofuranose produced by the processof claim
 18. 22. A process for deoxofluorinating a C₂-hydroxyl group ofa furanose, said process comprising: mixing said furanose and adeoxofluorinating agent in a solvent to form a reaction mixture; andheating said reaction mixture, wherein said deoxofluorinating agent isan aminosulfur trifluoride.
 23. The process of claim 22, wherein saiddeoxofluorinating agent is at least one member selected from the groupconsisting of diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, perfluorobutanesulfonyl fluoride,2-chloro-1,2,3-trifluoroethyldiethylamine and hexafluoroisopropyldiethylamine.
 24. The process of claim 23, wherein saiddeoxofluorinating agent is bis(2-methoxyethyl) aminosulfur trifluoride.